The spinal neuronal circuitry that subserves nociception and nerve injury is composed of three parts: intrinsic spinal neurons that are either local circuit neurons or projection neurons; the terminals of primary afferent neurons that carry inputs from the periphery; and axon terminals that descend to the spinal cord from the brain. Activity in these circuits is the basis for modulation of the neuronal output from the spinal cord. Using a variety of cellular and molecular techniques we have studied changes in gene expression in animal models of pain and nerve injury. Dynorphin, an opioid peptide, has been shown to be exquisitely regulated during noxious stimulation. We have used changes in dynorphin gene expression as a molecular marker for activity in spinal pain circuits. In a new animal model of pain developed in our branch, the Neuritis model, we have demonstrated an induction of dynorphin mRNA that correlates with the appearance of pain behavior. However, in comparing the dynorphin induction timecourse in the Chronic Constriction Injury model, both thermal and mechanical hyperalgesia are detected after the dynorphin mRNA induction. The descending control exerted by higher centers of the neuraxis on spinal nociceptive neural circuits represents a mechanism whereby the brain can control the production of nociceptive messages that are the output of spinal nociceptive processing. In our study of spinal pain circuits after removal of axons which descend from the brain, we identified a net inhibitory effect of descending axons on the opioid mRNA induction in response to painful stimulation. However, this net effect was unlikely to be mediated by monoaminergic neurons in the brainstem as removing serotoninergic and noradrenergic axons had no effect on the dynorphin mRNA induction in response to painful stimuli. Our studies on signal transduction in the dorsal root ganglia during the development of chronic pain have recently demonstrated that members of the STAT transcription factor family (Signal Transducers and Activators of Transcription) are regulated by noxious input. Gelshift analyses of extracts from dorsal root ganglia (DRG) identified an increase in the binding of STAT-like proteins to a STAT1 consensus sequence on the ipsilateral side to the painful stimulus. Our studies are the first to identify a transcription factor in the DRG that exhibits changes in animal models of pain.